Diabetes mellitus is a metabolic disorder in which the ability to utilize glucose is partly or completely lost. About 5% of all people suffer from diabetes and the disorder approaches epidemic proportions. Since the introduction of insulin in the 1920's, continuous efforts have been made to improve the treatment of diabetes mellitus.
One peptide expected to become very important in the treatment of diabetes is glucagon-like peptide-1 (GLP-1). Human GLP-1 is a 37 amino acid residue peptide originating from pre-proglucagon which is synthesized i.a. in the L-cells in the distal ileum, in the pancreas and in the brain. GLP-1 is an important gut hormone with regulatory function in glucose metabolism and gastrointestinal secretion and metabolism. GLP-1 stimulates insulin secretion in a glucose-dependant manner, stimulates insulin biosynthesis, promotes beta cell rescue, decreases glucagon secretion, gastric emptying and food intake. Human GLP-1 is hydrolysed to GLP-1(7-37) and GLP-1(7-36)-amide which are both insulinotropic peptides. A simple system is used to describe fragments and analogues of this peptide. Thus, for example, [Gly8]GLP-1(7-37) designates an analogue of GLP-1(7-37) formally derived from GLP-1(7-37) by substituting the naturally occurring amino acid residue in position 8 (Ala) by Gly. Similarly, (Nϵ34-tetradecanoyl)[Lys34]GLP-1(7-37) designates GLP-1(7-37) wherein the ϵ-amino group of the Lys residue in position 34 has been tetradecanoylated. PCT publications WO 98/08871 and WO 99/43706 disclose stable derivatives of GLP-1 analogues, which have a lipophilic substituent. These stable derivatives of GLP-1 analogues have a protracted profile of action compared to the corresponding GLP-1 analogues.
In the last decade a number of peptides have been isolated from the venom of the Gila monster lizards (Heloderma suspectum and Heloderma horridum). Exendin-4 is a 39 amino acid residue peptide isolated from the venom of Heloderma suspectum, and this peptide shares 52% homology with GLP-1(7-37) in the overlapping region. Exendin-4 is a potent GLP-1 receptor agonist which has been shown to stimulate insulin release and ensuing lowering of the blood glucose level when injected into dogs. The group of exendin-4(1-39), certain fragments thereof, analogs thereof and derivatives thereof, are potent insulinotropic agents. Most importantly the group of exendin-4(1-39), insulinotropic fragments thereof, insulinotropic analogs thereof and insulinotropic derivatives thereof.
Common to GLP-1 and exendins are that an extensive amount of variants have been synthesized and studied in particular in relation the plasma half-life. Low plasma half-lifes may be due to chemical stability towards peptidases (mainly dipeptidyl aminopeptidase IV) and to renal clearance. However, these analogues and derivatives of insulionotropic peptides lack a satisfactory bioavailability when administered by the pulmonary route, i.e. when administered to the lower respiratory tract such as through the bronchioles or alveoli.
WO 00/66629 discloses modified exendin agonists which have been coupled to polyethyleneglycol via a lysine residue to decrease renal clearance.
WO 03/40309 discloses peptide acting as both GLP-1 receptor agonists and glucagon receptor antagonists. Among the disclosed peptides are two peptides which have been coupled to polyethyleneglycol via a C-terminal cycleine residue.
WO 2004/093823 discloses polyethylene glycolated GLOP-1 peptides.
Pulmonary administration of GLP-1 peptides have been disclosed in WO 01/51071 and WO 00/12116.
The insulinotropic peptides derived from GLP-1 and Exendin-4 stimulated insulin release only when plasma glucose levels are high, the risk of hypoglycemic events is reduced. Thus, the peptides are particularly useful for patients with diabetes who no longer respond to OHA's (oral hyperglycemic agents) and who should from a strict medical point of view be administered insulin. Patients and to some extent also doctors are often not keen on initiating insulin treatment before this is absolutely necessary, presumably because of the fear of hypoglycemic events or the fear of injections/needles. Thus, there is a need for insulinotropic peptides which are sufficiently potent and which can be administered by the pulmonary route. Thus, it is an object of the present invention to provide insulinotropic peptides which have sufficient pulmonary bioavailability to serve as an alternative to peptides for parenteral administration. Insulinotropic peptides having pulmonary bioavailability is a balance between potency and bioavailability. It is also an object of the present invention to provide insulinotropic peptides which are less prone to aggregation, a well known problem associated with the glucagon-like peptides. Being less prone to aggregation facilitates economical manufacturing processes as well as enabling the compounds to be administered by medical infusion pumps.